Inter-Strain Variation in Murine Models of Leukemia

To the Editor:

The perspectives article, “Seed Versus Soil: The Importance of the Target Cell for Transgenic Models of Human Leukemias,” by Westervelt and Ley,1 highlighted a number of important issues regarding the use of transgenic murine models for leukemia research. One, the potential role of variation among mouse strains, was alluded to in the discussion of data from several PML/RARA fusion gene models of acute promyelocytic leukemia in which the investigators state that “the potential role of mouse strain differences contributing to the different observed phenotypes cannot be formally excluded at this time.” Indeed, several inbred strains of mice have been shown to exhibit significant differences in the levels of hematopoietic stem cells (HSCs) in bone marrow, as measured by long-term culture-initiating cell assay (LTC-IC), with C57BL/6 (B) and DBA/2 (D) mice differing by more than 10-fold and BALB/c (C) at intermediate levels.2 The variables causing such striking inter-strain differences in HSC levels may also be expected to exert some influence on the phenotypic effects due to the expression of a leukemia-related transgene in the HSC cell compartment.

Inter-strain variation in murine HSC levels may also be exploited to identify such variables. Performing a genetic reanalysis with current mapping information of previous data from 26 BXD recombinant inbred (RI) strains2 with MapManager software,3 using an additive regression model with no control for other quantitative trait loci (QTLs), has nominated 12 loci on 6 chromosomes at theP < .01 level linked to HSC level (Table 1). Several interesting candidate genes with potential relevance to HSCs that map close to nominated QTLs were also identified. Although the RI approach can be fraught with false-positive results and require confirmation, QTL nominations near 2 chemokine genes on chromosome 1, an interleukin gene cluster and granulocyte-macrophage colony-stimulating factor on chromosome 11, and a small inducible cytokine gene complex on chromosome 11, are highly suggestive and supported by functional approaches,4-6 including the recent demonstration of the role of chemokine receptor 4 (CXCR4) in hematopoietic reconstitution of human HSCs in immune deficient mice.7 Such data suggest that the inter-strain variation in HSC levels may be multifactorial and that the murine host may not be a passive nonparticipant in either transgenic or HSC engraftment and repopulation experiments. The identification of the specific inter-strain differences related to HSCs may, thus, be important in the design and interpretation of murine transgenic models of leukemias.